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Abstract

Dengue is the most important arthropod-borne viral disease of public health significance.
Compared with nine reporting countries in the 1950s, today the geographic distribution
includes more than 100 countries worldwide. Many of these had not reported dengue
for 20 or more years and several have no known history of the disease. The World Health
Organization estimates that more than 2.5 billion people are at risk of dengue infection.
First recognised in the 1950s, it has become a leading cause of child mortality in
several Asian and South American countries.

This paper reviews the changing epidemiology of the disease, focusing on host and
societal factors and drawing on national and regional journals as well as international
publications. It does not include vaccine and vector issues. We have selected areas
where the literature raises challenges to prevailing views and those that are key
for improved service delivery in poor countries.

Shifts in modal age, rural spread, and social and biological determinants of race-
and sex-related susceptibility have major implications for health services. Behavioural
risk factors, individual determinants of outcome and leading indicators of severe
illness are poorly understood, compromising effectiveness of control programmes. Early
detection and case management practices were noted as a critical factor for survival.
Inadequacy of sound statistical methods compromised conclusions on case fatality or
disease-specific mortality rates, especially since the data were often based on hospitalised
patients who actively sought care in tertiary centres.

Well-targeted operational research, such as population-based epidemiological studies
with clear operational objectives, is urgently needed to make progress in control
and prevention.

Introduction

Dengue is the most important arthropod-borne viral disease of public health significance.
Compared to nine reporting countries in the 1950s, today the geographic distribution
includes more than 100 countries worldwide. Many of these had not reported dengue
for 20 or more years and several have no known history of the disease. The World Health
Organization (WHO) estimates that more than 2.5 billion people are at risk of dengue
infection. Most will have asymptomatic infections. The disease manifestations range
from an influenza-like disease known as dengue fever (DF) to a severe, sometimes fatal
disease characterised by haemorrhage and shock, known as dengue hemorrhagic fever/dengue
shock syndrome (DHF/DSS), which is on the increase. Dengue fever and dengue haemorrhagic
fever/dengue shock syndrome are caused by the four viral serotypes transmitted from
viraemic to susceptible humans mainly by bites of Aedes aegypti and Aedes albopictus mosquito species. Recovery from infection by one serotype provides lifelong immunity
against that serotype but confers only partial and transient protection against subsequent
infection by the other three. First recognised in the 1950s, it has become a leading
cause of child mortality in several Asian and South American countries.

The average number of DF/DHF cases reported to WHO per year has risen from 908 between
1950 and 1959 to 514,139 between 1990 and 1999. The real figure is estimated to be
closer to 50 million cases a year causing 24,000 deaths. Of an estimated 500,000 cases
of DHF/DSS requiring hospitalisation each year, roughly 5% die according to WHO statistics.
Regional distribution of dengue and its serotypes are described elsewhere [1,2]. In summary, DF/DHF/DSS is an immediate problem in south and southeast Asia and Central
and South America. Although DF is present in the African region, there are no cases
or outbreaks reported to WHO [3].

Half the world's population lives in countries endemic for dengue, underscoring the
urgency to find solutions for dengue control. The consequence of simple DF is loss
of workdays for communities dependent on wage labour. The consequence of severe illness
is high mortality rates, since tertiary level care required for DHF/DSS management
is beyond the reach of most of the persons at risk.

This paper reviews the changing epidemiology of the disease, focusing on host and
societal factors and drawing on national and regional journals as well as international
publications. It does not include vaccine and vector issues. Although each one of
the issues taken up below merits an independent, in-depth treatment, we have selected
only those issues where the literature raises challenges to prevailing views and therefore
require further research, particularly given that most of these issues are key for
improved service delivery in poor countries.

Analysis

Clinical presentation

Dengue infection can cause a spectrum of illness ranging from mild, undifferentiated
fever to illness up to 7 days' duration with high fever, severe headache, retro-orbital
pain, arthralgia and rash, but rarely causing death. Dengue Haemorrhagic Fever (DHF),
a deadly complication, includes haemorrhagic tendencies, thrombocytopenia and plasma
leakage. Dengue Shock Syndrome (DSS) includes all the above criteria plus circulatory
failure, hypotension for age and low pulse pressure. DHF and DSS are potentially deadly
but patients with early diagnosis and appropriate therapy can recover with no sequelae.
Case management for DF is symptomatic and supportive. DHF requires continuous monitoring
of vital signs and urine output. DSS is a medical emergency that requires intensive
care unit hospitalisation [4].

The increase in dengue mortality is considered to be a reflection of the increase
in the proportion of DF patients who develop DHF/DSS. The pathogenesis of DHF/DSS
is widely considered to be antibody-dependent enhancement in secondary infection with
a virus of different serotype [5]. Evidence in support of this comes from many studies including from the Cuban epidemics
of 1981 and 1997 [5,6] and a five-year study of Yangon (Myanmar) [7]. However, absence of a significant association between secondary infection or co-circulation
of different serotypes and DHF/DSS has also been noted [8,9]. The disease is widely considered to be associated with secondary infection and co-circulation
of several serotypes.

Alternative or additional factors associated with severe illness, such as high viraemia
titres, have also been suggested [10]. So far, this has been associated with secondary infection as demonstrated by Vaughn
et al., and Libraty et al. [11,12]. On the other hand, one expression of higher viral virulence could be higher viraemia
leading to greater severity, but this has not not yet been demonstrated (Guzmán, 2003
personal communication).

Viral virulence [13], immunological responses and increased pathogenicity of specific serotypes [14] have been implicated as critical for the appearance of DHF. This has been found for
the three serotypes DEN1, [13] DEN 2 [15] and DEN 3 [8,10,16,17], but so far not for DEN 4 [18].

The evidence from different studies also shows that the pathogenesis of DHF/DSS may
be multi-factorial and understanding remains incomplete.

Epidemiological changes

Demographic, economic, behavioural and social factors are often keys for effective
communicable disease control and underpin successful public health programmes. Despite
promising indications in the literature, these factors have remained poorly understood
in the case of dengue. Furthermore, recent field evidence raises some questions regarding
widely accepted characteristics of dengue that need review and confirmation.

Shift in modal age

DF is typically acknowledged to be a childhood disease and is an important cause of
paediatric hospitalisation in southeast Asia. There is, however, evidence of increasing
incidence of DHF among older age groups. Since the early 1980s, several studies in
both Latin America and southeast Asia have reported a higher association of DHF with
older ages. The earliest studies were by Guzmán (1981) in Cuba and Rigau-Pérez in
Puerto Rico [6,19]. Later on similar observations were noted in Nicaragua and Brazil. In some southeast
Asian countries where dengue has been epidemic for several years, this age shift is
clearly observed, indicating an epidemiological change in dengue infection in those
locations [20-22].

Three studies in Asia using surveillance data report increasing age of infected patients.
In Singapore, surveillance data showed a shift in peak dengue mortality from paediatric
ages (1973–1977) to adults in 1982, since which year more than 50% of the deaths occurred
in patients older than 15 years. From 1990–96, the highest age-specific morbidity
rates were in the 15 to 34 year age groups [23]. In Indonesia, surveillance data from 1975 to 1984 showed an increase in incidence
rates among young adults in Jakarta as well as in the provincial areas [24]. Adults have accounted for proportions as high 82% of all cases in the hospital-based
surveillance study during the 2000 epidemic of dengue in Bangladesh [25]; the highest proportion of cases occurred in the 18 to 33 year age group. All deaths
in the Bangladesh outbreak in 2000 were in persons older than 5 years. In Puerto Rico,
surveillance data analysis showed the highest incidence rate (11.8/1000) in the 10–19
year age group during an outbreak in 1994 and 1995 [26].

Hospital-based studies have similarly reported increasing infection rates among adults,
mentioning that it is contrary to the popular belief that dengue is a paediatric disease
[27,28]. The trend for increased incidence among young adults has important implications
for control and prevention. Whether these are real increases (based on population
distributions), increases in the proportion of DHF/DSS (and, hence, the proportion
hospitalised) but not DF, or the result of improved classification and diagnosis needs
clarification. Comparative incidence and case fatality ratios (CFRs) of severe illness
in adults and children and the economic implications are discussed later.

Racial predisposition

Race-related susceptibility to dengue has been observed in a few studies and merits
further investigation. In a retrospective seroepidemiologic study Guzmán reported
that blacks and whites were equally infected with DEN-1 and DEN-2 viruses during the
Cuban epidemics of 1977 and 1981, while severe dengue disease was observed less frequently
in dengue-infected black persons than whites [5,6].

A study in Haiti observed that despite virologic pre-conditions hypothesised to be
precursors for DHF (i.e. the evidence of previous infection by DEN virus types 1,
2 and 4), local children did not develop severe illness [29]. The authors concluded that this finding provides further evidence of a dengue-resistant
genotype in black populations. In 1998 the Los Angeles County vital registration system
reported DF/DHF incidence, but only among Hispanic and white ethnic groups (0.1 and
0.07/100,000) [30].

Genetic polymorphism in cytokine profiles and coagulation proteins has been proposed
as a factor protecting persons of African origin [31]. Evidence for this hypothesis has been found in meningococcal disease, in which a
genetic polymorphism in the gene encoding an essential protein involved in coagulation
is a predictor for developing severe disease with lethal outcome.

In Asia, two studies report racial differences in disease incidence. A 15-year study
of the epidemiology of dengue reports a significantly higher incidence of DHF among
Chinese compared to Malaysian males [32]. This finding was supported by a six-year surveillance data study in Singapore, which
found the race-specific morbidity rate among the Chinese to be three times that of
the Malays and 1.7 times that of Indians [23]. Although none of the above constitutes convincing evidence for the hypotheses, they
highlight a useful area for better understanding of dengue pathogenesis and health
service planning.

Sex differences

Understanding male-female differences in infection rates and severity of disease is
important for public health control programmes. A few hospital-based studies and surveillance
data show a male-female difference in infection rates and in severity of disease.
Three independent studies from epidemics in India and Singapore found nearly twice
the number of male patients compared to females (Lucknow and Singapore both report
male to female ratios of 1.9:1 and Delhi 1:0.57) [33-35]. In his hospital-based study during the 1996 epidemic in Delhi, Wali reported an
even higher ratio of 2.5:1 [27]. Another study during the same epidemic found a male to female ratio of 1:0.25 cases
for DSS. However, of the three deaths in this sample, two were female [35]. Surveillance data from Malaysia revealed a male preponderance among Indian and Malay
patients (1.5:1), but the ratio was almost equal for those of Chinese origin [32]. The Ministry of Health, Bangladesh reported a hospital patient DF/DHF male to female
ratio of 1.5:1 during an outbreak in Chittagong in 1997 [36], although a later study of DHF only during the 2000 outbreak found no differences
between sexes [37]. With the exception of the study by Shekhar, all the others were hospital-based and
may represent those who sought care rather than the infected population [27].

Studies in South America generally report that both sexes are equally affected [26,38] although a male to female ratio of 0.65:1 was described as "typical" for dengue [9]. Kaplan, in a rare study testing for significance, found a higher proportion of women
in all of his four Mexican samples (p < 0.001) [39].

Of significance are two studies in Asia by Kabra and Shekhar where severe illness
and CFR were consistently higher among females despite higher incidence in males [32,40]. Halstead [41] had pointed out as early as 1970 that males predominate among those with milder disease
but females account for more severe illness. He suggested that either immune responses
in females are more competent than in males, resulting in greater production of cytokines,
or the capillary bed of females is prone to increased permeability. Kaplan in Mexico
suggests that an incidence bias in favour of females is related to the timing of the
survey interviews, while Goh puts forward that low incidence among women occurs because
they stay at home and are less exposed to infection [39,42].

No studies suggest gender bias in home care and male preferences in health care seeking,
still prevalent in many Asian and other traditional societies. It is widely recognised
that in many of the Asian communities, lower disease incidence in women may be a statistical
artefact related to lower reporting and care-seeking for women from traditional practitioners
who do not report to public surveillance systems. By the same token, women are less
likely to be taken for care at a hospital when ill or are taken at late stages of
disease, when no other options are available. Determining sex differences, both in
infection and severity of disease, requires well-designed and targeted studies to
capture both biological and social factors that drive disease patterns in a community.

Rural spread

Historically, DF/DHF has been reported as occurring predominantly among urban populations
where density of dwellings and short flying distance of the vector create the right
conditions for transmission. However, the literature shows that dengue transmission
and, in some cases, outbreaks occur in rural settings in both Asia and Latin America.
In the WHO Western Pacific region, WHO has confirmed that disease spread into rural
areas from where it had not been reported previously [20].

Rural epidemics occurred as early as 1976 in Indonesia, and in 1994 the outbreak in
Laos began in a remote, rural district of Nasaithong [43,44]. Today, Thailand has an incidence rate that is higher in rural (102.2 per 100,000)
than urban areas (95.4 per 100,000) [28]. Similarly, in India, entomological investigation showed a widespread distribution
of Aedes aegypti, both in rural and urban areas during an outbreak in Gujarat in 1988 and 1989 [45]. Increase in DF/DHF among rural populations is also observed in Central and South
America and identical rates in both populations are reported [9]. Among jungle dwellers in Peru, antibody prevalence up to 67% compared to 66% among
the urban population have been found [46].

In industrialised settings, the Centers for Disease Control and Prevention (CDC) reported
an outbreak of DF among residents of the rural towns of Hana and Nahiku in Hawaii
in 2001. The outbreak was historically unusual because infection occurred among residents
who have no history of recent travel and the Aedes aegypti mosquito has not been seen in Hawaii since it was supposedly eradicated by pesticide
spraying in 1943 [47].

Increased transport contact, mobility and spread of peri-urbanisation have been the
most frequently cited reasons for spread of dengue to rural areas [48]. While some rural incidence linked to travel contact with urban areas is conceivable,
outbreaks and infection rates equal to those in urban areas warrant further investigation.
Improved reporting could also be a factor, but it would be less likely in areas such
as Hawaii, USA. Standard epidemiological techniques such as spatial studies of cases
and careful patient histories could shed further light into transmission patterns
in rural populations. Health service structures and utilisation patterns differ substantially
between urban and rural areas in many tropical countries and contextually appropriate
strategies will be required for effective impact.

Seasonality and climate variability

The incidence and, in particular, epidemics of dengue have been commonly associated
with the rainy season, and the El Niño phenomenon has been incriminated in the increases
of certain vector-borne diseases, including dengue [49,50].

Despite the number of studies, convincing data or models supporting these hypotheses
are scarce. The relationship between temperature, rainfall and vector-borne disease
are increasingly seen as oversimplifications. A study modelling DF transmission and
seasonal temperature on data from Puerto Rico from 1988 to 1992 revealed weak relationships
between monthly mean temperature and incidence of DF [51]. The study concluded that factors related to history of herd immunity, introduction
of new serotype or demographic transitions influence transmission.

More recently, long-term meteorological trends were studied in four high-altitude
sites in East Africa, where increases in malaria have been reported in the past two
decades [52]. They did not observe any significant change in temperature, rainfall, vapour pressure
and the number of months suitable for P. falciparum transmission in the past century or during the period of reported malaria resurgence.
Others have questioned models linking global temperatures and disease incidence, stating
that, historically, climate has rarely been the principal determinant of vector-borne
disease prevalence. Neither does the literature provide an adequate evidence base
establishing the impact of climate change on vector-borne disease [53,54]. The "bandwagon" of El Niño [55] and dengue incidence is now placed under scrutiny and further research will have
to be done before climate variations can be nailed down as a culprit.

Health systems issues

Socio-economic context

Social and economic factors play an essential role in the incidence and prevalence
of DF and DHF. Air conditioning, screens and safe water supplies in wealthier countries
help prevention and better health services reduce or eliminate mortality from DHF.
Unplanned urbanisation and inadequate resources for vector control are factors that
promote transmission and are characteristic of poor rather than richer countries.
Reiter et al. (2003) studied dengue transmission on the Mexico-USA border and found higher rates
in the Mexican city compared to the American one [56].

However, some anomalies persist despite the rich/poor divide in disease incidence.
Despite energetic control programs in the wealthier endemic countries of southeast
Asia such as Singapore, Malaysia and parts of China (eg. Hong Kong), dengue continues
to be a problem. Malaysia reports some of the highest numbers of cases during epidemics
compared to other countries in the region. In some of these cases, particular traditional
practices, such as rainwater storage on roofs, expose them to higher risk.

The major epidemic in Puerto Rico in 1977 serves as a reminder that advanced public
health capacities and economic development may not guarantee protection against massive
epidemics [9]. Despite high quality of health services and richer circumstances, complacency in
endemic countries may lead to increased rates without continued vigilance.

On an individual level, evidence points to greater susceptibility among well-nourished
or middle-class communities rather than malnourished and poorer patients commonly
associated with other tropical diseases.

A case-control study of serologically-confirmed DHF patients, other infectious diseases
patients and healthy children in the Children's Hospital in Bangkok showed that malnutrition
amongst DHF patients was significantly lower [57]. In India, a hospital-based study found no association between nutritional status
and severity of illness [40].

Middle classes have been specifically noted as the proportionally predominant group
during the epidemic in Dhaka Bangladesh [25] and upper social classes had statistically higher sero-infection rates in Fortaleza
and San Luis epidemics in Brazil [38]. Confounding factors for the preponderance of DF/DHF among the upper classes or well-nourished
dengue patients were not discussed in any of these studies.

Few studies specifically measure and test socio-economic determinants of exposure
at community levels. Heukelbach in Fortaleza, Brazil did examine socio-economic variables
but their study did not show an association with DF [58]. Since all 34 cases selected were from a shanty town (favela), a lack of heterogeneity
may have been a factor for this result rather than a real absence of difference. In
Taiwan, Ko, also in a case-control study, observed that patients who lived near markets
and/or open sewers or ditches had a risk of contracting disease 1.8 times higher than
those who did not [59]. Since housing near sewers and ditches is likely to comprise poorer families, the
analysis should have tested for house site while controlling for use of screens, which
were significantly associated with incidence.

Costs

On a macro level, the impact of dengue on the economy is likely to be increasingly
similar to that of malaria. Prevalent in communities characterised by subsistence
or daily wage labour, a week's illness can be catastrophic for poor families. As a
primarily paediatric disease in the past, the active labour force or the family wage
earners were less affected. Now, as the modal age of illness and incidence increases,
losses in productivity and earning capacity may be expected. The economic lesson from
malaria was learnt late and when the resurgence was already in full swing. Dengue
fever risks the same fate.

With regard to costs of care, few economic studies exist and most estimate economic
loss to range in millions. Von Allmen et al. undertook a cost analysis of the epidemic of DF/DHF in Puerto Rico in 1977 using
upper and lower limits of incidence [60]. They estimated the direct costs (medical care and epidemic control measures) to
range between US$2.4 and $4.7 million and indirect costs (lost production of patients
and parents of children) between US$6 and $15 million. Another economic study, still
in Puerto Rico, assessed the loss in terms of DALYs due to dengue [61]. At 658 DALYs per year per million population, the study concluded that, in terms
of its magnitude, DF ranks with TB, STDs (including HIV), childhood diseases or malaria.

On a micro level, a detailed study on costs of care in 3 hospitals in Bangkok estimated
direct adult patient costs at US$67. Including opportunity costs, this figure increased
to US$161.49. The net hospital cost for each DHF patient was US$54.60 and the public
sector cost of prevention and control of the outbreak was US$4.87 million. The total
expenditure for DHF in 1994 was estimated to be at least US$12.56 million, of which
45% was borne by the patients [62].

These figures are reminders that most of the countries subject to DF/DHF cannot realistically
afford a US$5 million prevention and control budget for a single disease and that
the monthly income of many families in these countries is less than the direct cost
of US$70 a month.

Knowledge, attitude and practice (KAP)

Much needs to be done in finding effective strategies for behaviour change. Since
mothers are the first-line care-givers, this aspect is key, particularly for childhood
diseases. KAP studies are rare and therefore little is known regarding knowledge and
attitude of the exposed population towards dengue. However, the little that is known
is encouraging.

Straightforward community education to reduce breeding sites for mosquitoes performed
better than chemical spraying in a controlled experiment in Mexico [63]. However, housewives, the unemployed and the elderly had significantly lower levels
of knowledge of the disease compared to students and persons of younger ages (odds
ratio (OR) = 0.44, 95% confidence interval (CI): 0.31–0.64). Other KAP studies have
found that radio and television are very effective channels for knowledge dissemination.
Nevertheless, these same studies found that while communities can score well in knowledge
of the disease, they perform less well in attitude and practice, indicating that behaviour
change is one area to target in social mobilisation programmes [64-67].

Treatment-seeking behaviour and lay symptom assessment is the first step in the chain
to early diagnosis and was found to have an impact on duration of illness in Thailand
[68]. In that context, it is discouraging to note that 45% of individuals in a population-based
survey (23,970 households) in the urban municipality of Vientiane did not know what
action to take when their children are diagnosed with dengue or what they should do
for prevention [44].

Finally, reducing mortality from DHF and strengthening its control and prevention
clearly cannot be done by the population alone. In most circumstances, these are poor
populations with other pressing agendas. The programme requires public sector leadership
with strong intersectoral collaboration. The WHO has made important progress to determine
ways and mechanisms through which to achieve collaboration between sectors and state
policy directions for control.

Trends in case fatality rates

Two aspects present themselves for useful discussion in this area. One relates to
wide variations in CFRs between countries, sub-national units and hospitals under
similar virological conditions. The other relates to differential risks of severe
illness and mortality between children and adults.

The global case-fatality rate (CFR) for DHF/DSS has been declining in most of the
endemic countries according to government statistics. The overall CFR in the southeast
Asia region is now less than 1% [20]. However, disaggregated data reveal a different picture. Rates vary significantly
between countries, provinces and hospitals, pointing to a more complex situation.

From 1995–2000, the CFR in the countries of WHO Western Pacific Region ranged from
0.06% in Singapore and 0.17% in Malaysia to 3.4% in Cambodia. Hong Kong reported no
deaths [69]. In Vietnam, province-based 1998 data for DHF show CFR ranging from nearly 13% in
Ha Tinh to 0.5% in Quang Tri [70]. Although the four provinces with the highest CFR were at some distance from Ho Chi
Minh City or Hanoi, the four of the lowest were not particularly closer to these centres
of tertiary care. In Laos, on the other hand, CFR for DHF during 1998 reached a high
of 9.7% in Champassak province compared to 1.4% in Municipality of the capital city,
Vientiane [44]. Wide variation in CFRs ranging from 0.1% to 5%, was also noted between the first
administrative divisions in the Philippines [71].

During the 1998 epidemic in Cambodia the CFR in Kantha Bopha, a private, charitable
hospital, was substantially lower (1.96%) than the national average (2.91%) [70]. Inter-district and inter-hospital variation is generally indicative of quality of
care. Availability of medical supplies, equipment and economic status of patients
can explain some differences but analyses to distinguish between the performances
of provinces and countries in comparable settings would be useful for designing more
effective disease control.

Secondly, studies have postulated higher risk of DF/DHF morbidity and mortality among
children compared to adults [15]. Recently, increasing reports of severe illness among adults and in some cases higher
CFRs (e.g. age-specific CFRs from San Lazaro hospital over one year were 3.8% for
35–39 year olds, 8% for over 45s compared with 2% and 2.6% for 0–4 and 5–9 year age
groups) merit closer looks at determinants of adult mortality [37,71,72].

Case management and early detection

In addition to vector control, widely recognised as a preventive strategy of choice,
key health sector response for reduction of mortality and morbidity lies primarily
in two areas: early detection (including care-seeking behaviour change and better
surveillance) and improved case management of patients. Mortality in excess of 1%
may be considered the consequence of inadequate care, late diagnosis and delayed hospitalisation.

A hospital-based study during the dengue outbreak in Delhi revealed that mortality
could be very low in patients who came early to the hospital [73]. Late presentation was also strongly associated with increased mortality in children
with DHF in the Philippines [74].

The short interval between onset of haemorrhage and death, especially in young children,
makes rapid medical intervention for DHF/DSS a critical factor for survival. For most
communities at highest risk of disease, intensive care facilities are only available
at distant capitals requiring motorised transport, usually beyond the reach of many.
Early diagnosis and leading indicators for DHF/DSS can ensure the availability of
travel time to transfer the patient for effective treatment. Case-control studies
have shown that low-normal hematocrit count at time of shock is a significant risk
factor for haemorrhage [75] and potential predictors for clinical outcome, such as decrease in total plasma cholesterol,
and high- and low-density lipoprotein, were associated with the severest cases [76].

However, research into predictive factors for severe illness is neither abundant nor
conclusive. Moreover, as Van Gorp concludes, low capacity and lack of resources at
secondary levels of health services limit the operational use of many of these findings
[76].

At this time, the WHO classification of dengue diseases is often not feasible in many
countries because of lack of trained health professionals, inadequate laboratories,
and radiological support. Neither are facilities to detect DHF by using hematocrit
and plasma leakage signs readily available in many tropical countries. As successful
treatment of dengue depends on symptom recognition and careful fluid management, a
simpler dengue disease classification scheme, realistic in poor, provincial conditions
and better training of district-level personnel is needed.

A few creative approaches to primary health care to improve quality of care and case
management at primary health care levels have been reported in the literature. For
example, encouraging results have been found in Vietnam where they reduced dengue
mortality rates by 64% through innovative primary healthcare concepts, including paediatric
priority training units for medical staff, health education for patient carers and
promotion of outpatient treatment to avoid unnecessary admissions [77]. Reduction of CFRs from 10–15% (40% in some areas) in the early 1950s to less than
0.5% today in east Asian referral hospitals have been attributed to better training
of the hospital staff [78].

The effect of strengthened health systems is recognised by public health authorities
including WHO but is missing operational research and policies to put them into effect.

Surveillance and reporting

Unreliable statistics are an extremely serious weakness from many perspectives. Estimates
of DHF/DSS CFR from surveillance data are consistently lower than those from single
sample study data suggesting under-reporting or misclassification of deaths. Inadequate
knowledge of case definitions among district health personnel compromise complete
reporting even within the public health service system. Inappropriate denominators
further add to the confusion in estimating prevalence and incidences.

Reporting deviations can lead to seriously misleading CFRs in countries where reliable
estimates are urgently needed for effective resource programming. In Laos, for instance,
8197 DHF cases and 24 deaths were registered by the WHO in 1996, compared to 2563
cases and 23 deaths registered by the Institute of Malariology, Parasitology and Entomology
(IMPE) for a CFR of that is 3 times higher than WHO statistics [22], Most national surveillance data rely only on public sector institution reporting.

An evaluation of the dengue reporting system in Bandung, Indonesia (covering private
and public hospitals) found that only 31% of hospitalised DHF/DSS cases were reported
to the Municipal Health Authorities [79]. In Puerto Rico, a hospital record review revealed a ratio of 3:1 total DHF cases
compared to those detected by surveillance [80]. More alarmingly, in Texas, USA, an
assessment of underdiagnosis of dengue was undertaken motivated by an outbreak in
a town across the border in Mexico. A review of medical records between 23 July and
20 August 1999 found that 50% of suspected cases had undiagnosed dengue infection.
[81].

Based on the above studies, a conservative estimate would be that a third of the total
cases are captured by surveillance systems, indicating that the global incidence rate
could be around 1.5 million cases of DHF on an average year rather than the 0.5 million
estimated by WHO.

While complete surveillance data may be an unrealistic option in many the affected
countries, sentinel surveillance and sample surveys using reliable methodologies could
be undertaken to provide more accurate estimates of the disease burden and fill in
the gaps. Occasional sample surveys of the private sector could help better estimate
the bias in disease burden.

Conclusion

On 18 May 2002, the WHO General Assembly confirmed dengue fever as a matter of international
public health priority through a resolution to strengthen dengue control and research.

Today, changing characteristics of the disease deserve serious research attention.
Shifts in modal age, rural spread, social and biological determinants of race- and
sex-related susceptibility have major implications for health service planning and
control strategies. Behavioural risk factors, individual determinants of outcome and
leading indicators of severe illness are poorly understood, compromising the effectiveness
of control programmes. Early detection and case management practices have been noted
as a critical factor for survival. Yet well-targeted operational research in these
areas is rare. Population-based epidemiological studies with clear operational objectives
should be launched as concerted efforts at regional levels.

A major weakness is the inadequacy of sound statistical methods in some of the reviewed
studies. Samples are exceedingly small in many cases, selection methods are often
inadequately described or are self selecting, tests of significance are frequently
not undertaken or not reported and denominators are not clearly described. Conclusions
therefore do not have the full benefit of objective statistical analyses, reducing
the scientific strength of the results. Furthermore, conclusions regarding case fatality
or disease-specific mortality rates are hard to draw since they are frequently based
on hospitalised patients who had actively sought care in tertiary centres. However,
a systematic approach and a clear international research agenda can quickly bring
forward the frontiers of knowledge. Better understanding of the above will not only
feed into operational policy for dengue control, but also provide fertile terrain
for vaccine application strategies in the future.

Today, dengue control and prevention requires thinking outside the tropical disease
box. Many of the affected countries are some of the poorest. Approaches that are realistic
for their infrastructure need to be urgently developed.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Debarati Guha-Sapir set out the plan of the paper, its focus areas and main messages.
Barbara Schimmer carried out the literature search, summarised the studies and their
results. She helped D. Guha-Sapir with the writing of the text.

Acknowledgements

Grateful acknowledgements are due to M. Nathan, S. Macfarlane and A. Karaoglou for
keeping us informed, involved and encouraged and Wilbert Van Panhuis for general research
assistance. The European Union Fifth Framework programme Contract no ICA4-CT-1999-50008
permitted us to undertake some of the basic epidemiological data reviews on the ground.

References

Summary of the dengue situation in the Western Pacific region Manilla, World Health Organisation Western Pacific Regional Office; 2001:9.